Potent benzimidazolone-based CGRP receptor antagonists.
The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.
Theberge
Cory R
CR
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. cory_theberge@merck.com
Bednar
Rodney A
RA
Bell
Ian M
IM
Corcoran
Halea A
HA
Fay
John F
JF
Hershey
James C
JC
Johnston
Victor K
VK
Kane
Stefanie A
SA
Mosser
Scott
S
Salvatore
Christopher A
CA
Williams
Theresa M
TM
Zartman
C Blair
CB
Zhang
Xu-Fang
XF
Graham
Samuel L
SL
Vacca
Joseph P
JP
D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007189:Indans / Q000737:chemistry*; D008253:Macaca mulatta; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007189:Indans; D013141:Spiro Compounds; C014353:benzimidazolone